The central theme of this proposal is the total synthesis of several decahydroquinoline alkaloids. This broad class of natural products is structurally diverse and complex, and many of these alkaloids possess powerful yet highly specific biological activity, the detailed investigation of which has considerable therapeutic implications. However, as they are often isolated from natural sources in meager quantities, a laboratory synthesis proves desirable and provides many additional benefits, such as confirmation of structure and elucidation of biosynthetic/metabolic pathways. More importantly, it can supply sufficient material for biological testing, and allows access to structural analogs that may in turn reveal the key pharmacophore. Therefore, continued development of new and varied methodology to aid in the total synthesis of alkaloid natural products remains of the utmost importance. The specific approach proposed herein involves one such nascent methodology - the utilization of N-substituted oxazolones as the dienophilic component in a novel intramolecular Diels-Alder cycloaddition. As this is a reaction originally developed in the P.I.'s laboratories, the proposed studies have ample precedent and preliminary results are both extensive and supportive. Our chosen targets are: (i) gephyrotoxin 287C, one of many poison dart frog alkaloids with intriguing and specific neuroexcitatory properties, and (ii) lepadins F an G, similar yet distinct marine metabolites with significant anti-malarial activity. For gephyrotoxi, the planned route hinges upon rapid construction of a densely functionalized cis-fused decahydroquinoline core containing 3 of the 5 required stereocenters. Already in hand, this framework will now serve as the key heterocyclic scaffold for all further elaboration to the final target itself. A number of innovative strategies will be employed to achieve this, including a 2-step cyclopropanation-ring scission approach to regio- and stereoselective installation of a required C6 substituent, and the tandem closure of a pyrrolidine ring by E2 excision of an oxazolidinone moiety followed by Michael cyclization. These studies, to be investigated in parallel, will employ a combination of new methodology and established precedent. Once the specific nature of these reaction paths is established, a direct route to the target will be finalied. A similar approach to the lepadin core differs slightly in that it features an electron-deficient 2 substituted diene, a system as yet untried in oxazolone Diels-Alders. A series of simple model studies will reveal the character of this cycloaddition [overall mode; effect/role of substituents] and the expected cycloadducts will then undergo further transformation to the target compounds. These efforts will therefore aid directly in the continued development of novel synthetic methodology for the total synthesis of bioactive alkaloids, and in doing so will provide numerous structurally related analogs for biological evaluation.